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Action of advanced glycation end products on the blood-brain barrier and its relationship with Alzheimer's disease

Grant number: 23/08210-6
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2023
Effective date (End): January 31, 2024
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal Investigator:Marimélia Aparecida Porcionatto
Grantee:Amanda Martins Story
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:18/12605-8 - Development of brain-on-a-chip microplataforms for in vitro modeling of the central nervous system, AP.TEM


Metabolic disorders, including diabetes mellitus (DM) and Alzheimer's disease (AD), comprise degenerative and multifactorial conditions that share pathophysiological processes, such as a deficit in glucose metabolism. In DM, there is a chronic accumulation of glucose in the blood, whereas, in AD, glucose has a hypometabolism that contributes to neuronal loss and impairment of synaptic plasticity together with plaques of amyloid beta oligomers (A²Os). However, the common mechanisms that trigger the pathogenesis of these two diseases remain elusive. As the progression of DM is implicated in the development of vascular and neurodegenerative complications, the exacerbated production and accumulation of advanced glycation end products (AGEs) have been highlighted as strong candidates for these events. AGEs are molecules formed by the glycation of proteins, lipids, and nucleic acids that are pathological in the diseases highlighted above. The interaction of AGEs with their receptors (RAGEs) in diabetic patients may contribute to the development of AD, favoring the breakdown of the integrity of the blood-brain barrier (BBB) and stimulating A²Os aggregation and damage to neurons. Thus, AGEs represent a group of molecules that trigger several pathways and processes that can elucidate how DM is involved in the onset of AD. In this project, the objective is to develop a microenvironment with excess AGEs and high glucose using a transwell insert containing endothelial cells (BBB cell model), astrocytes, and neurons in its composition, all derived from human induced pluripotency cells (hiPSCs). The presence of peptides derived from the APP protein (amyloid precursor protein) that may indicate a possible development of AD and the process of neuronal death will be evaluated. Thus, it is expected to develop a model capable of associating pathways, molecules, and cells involved in the close relationship between DM and AD.

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